The present invention concerns certain substituted pyridines, processes for the production thereof, and the use thereof in pharmaceutical products. It also concerns certain substituted biphenyls, processes for their production, pharmaceutical compositions containing them, and methods for their use.
7-(polysubstituted pyridyl) hept-6-enoates for the treatment of arteriosclerosis, lipoproteinemia, and hyperlipoproteinemia are known from U.S. Pat. No. 5,169,857. In addition, the production of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-hept-6-enoate is described in EP 325 130.
Glucagon is a peptide hormone whose main function is to increase hepatic glucose production. Insulin, on the other hand, functions to decrease glucose production. Together, these two hormones are necessary for maintaining a correct level of glucose in the blood.
Diabetes is a complex disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes is also associated with elevated glucagon levels. The heterogeneous nature of the disease requires different strategies to address the different abnormalities in metabolism found in affected individuals.
In the diabetic state (all forms of Type I and Type II), hyperglycemia often is associated with elevated glucagon levels. Accordingly, a means of treating all forms of diabetes is to block the glucagon receptor with a suitable antagonist, thereby inhibiting glucose production by the liver and reducing glucose levels in the patient.
Glucagon receptor antagonists, materials which block the action of endogenous glucagon, are known to have many and varied applications. Among these applications are the following:
1. Treatment of hyperglycemia associated with diabetes of any cause and associated with any other diseases or conditions. A glucagon receptor antagonist can be used either alone or in combination with any other therapies to treat hyperglycemia. PA1 2. Treatment of impaired glucose tolerance (IGT). PA1 3. Treatment of insulin resistance syndromes including those due to obesity, polycystic ovarian syndrome, "Syndrome X", drugs and hormones, endocrinopathies and genetic syndromes. PA1 4. To decrease free fatty acid levels and treat conditions associated with elevated free fatty acids levels such as insulin resistance, obesity, all or part of Syndrome X, Type I and II diabetes, hyperlipidemias and elevated hepatic glucose output associated with insulin resistance, Type I and Type II diabetes, obesity, and Syndrome X. PA1 5. To treat conditions associated with genetic defects in insulin action due to alterations in insulin receptor structure and function or alterations in post receptor signal transduction. To treat diabetes associated with anti-insulin antibodies, drug induced diabetes, diabetes associated with endocrinopathies and diabetes associated with genetic syndromes. PA1 6. To treat gestational diabetes mellitus. PA1 7. To treat autoimmune and non autoimmune causes of Type I diabetes including those due to known genetic defects of the beta cell, pancreatic diseases, drug or toxin induced beta cell dysfunction, endocrinopathies, infectious causes, malnutrition associated and idiopathic Type I diabetes. PA1 8. To prevent and treat diabetic ketoacidosis and decrease hepatic ketone body production PA1 9. To treat hyperglycemia of exercise in diabetes. PA1 10. To reduce fasting and postprandial glucose. PA1 11. Treatment of insulin resistance in liver, muscle, and fat. PA1 12. Treatment of conditions of hyperlipidemia. PA1 13. To treat glucagonomas and all other conditions associated with elevated glucagon levels. PA1 14. To treat conditions of increased futile cycling of glucose in the liver. PA1 15. To increase insulin secretion. PA1 16. To decrease glucose toxicity. PA1 17. To decrease the renal prostaglandin response to protein and amino acids. PA1 18. To decrease elevated GFR and albumin clearance due to diabetes or proteins or amino acids. PA1 19. To decrease renal albumin clearance and excretion. PA1 20. To treat acute pancreatitis. PA1 21. To treat cardiovascular disease including causes of increased cardiac contractility. PA1 22. To treat cardiac hypertrophy and its consequences. PA1 23. As a diagnostic agent and as a diagnostic agent to identify patients having a defect in the glucagon receptor. PA1 24. Treatment of gastrointestinal disorders, treatment of decreased gut motility. PA1 25. As a therapy to increase gastric acid secretions. PA1 26. To reverse intestinal hypomobility due to glucagon administration. PA1 27. To reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of Type I and Type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions. PA1 28. To treat any of the above conditions or diseases in post-operative or operative period. PA1 29. To decrease satiety and increase energy intake. PA1 A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula --NR.sup.1 R.sup.2, PA1 wherein PA1 D stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, PA1 E and L are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, PA1 or PA1 stand for cycloalkyl with 3 to 8 carbon atoms, PA1 E has the above-mentioned meaning PA1 L in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula --NR.sup.3 R.sup.4, PA1 wherein PA1 E stands for straight-chain or branched alkyl with up to 8 carbon atoms, or PA1 stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula --NR.sup.5 R.sup.6, PA1 wherein PA1 L in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, PA1 T stands for a radical of the formula ##STR3## PA1 wherein PA1 A stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula --NR.sup.2 R.sup.3 and/or --WR.sup.4, PA1 wherein PA1 D and E are identical or different and stand for a straight-chain or branched alkyl chain with up to 8 carbon atoms, PA1 E stands for a bond, PA1 V stands for an oxygen or sulfur atom or for a group of the formula --NR.sup.5 --, PA1 wherein PA1 R.sup.1 stands for cycloalkyl with 3 to 6 carbon atoms, or stands for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, optionally benzocondensed, saturated or unsaturated, mono-, bi-, or tricyclic heterocyclic compound with up to 4 carbon atoms from the series S, N, and/or O, PA1 in which the heterocycles, also via the N function in the case of nitrogen-containing rings, are optionally substituted up to 3 times in an identical manner or differently by halogen, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, by aryl with 6 to 10 carbon atoms, or by an optionally benzo-condensed, aromatic 5- to 7-member heterocyclic compound with up to 3 heterocyclic atoms from the series S, N, and/or O, and/or are substituted by a group of the formula --OR.sup.6, --SR.sup.7, --SO.sub.2 R.sup.8, or --NR.sup.9 R.sup.10, PA1 wherein PA1 L and T are identical or different and stand for trifluoromethyl or straight-chain or branched alkyl with up to 8 carbon atoms, which are optionally substituted by cycloalkyl with 3 to 7 carbon atoms, or by aryl with 6 to 10 carbon atoms, which in turn can be substituted up to 2 times in an identical manner or differently by halogen, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, PA1 L and/or T stand for cycloalkyl with 3 to 7 carbon atoms or stand for aryl with 6 to 10 carbon atoms or for a 5- to 7-member, saturated, partially unsaturated, or unsaturated heterocyclic compound with up to 3 heterocyclic atoms from the series S, N and/or O, with binding in the case of a nitrogen atom also being possible via this atom, with the heterocycles optionally being substituted up to 3 times in an identical manner or differently by halogen, nitro, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, PA1 A stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula --NR.sup.1 R.sup.2, PA1 wherein PA1 D stands for straight-chain or branched alkyl with up to 6 carbon atoms, which is substituted by hydroxy, PA1 E and L are either identical or different and stand for straight-chain or branched alkyl with up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, PA1 E has the above-mentioned meaning PA1 L in this case stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or by a group of the formula --NR.sup.3 R.sup.4, PA1 wherein PA1 E stands for straight-chain or branched alkyl with up to 5 carbon atoms, or stands for naphthyl or phenyl, which are optionally substituted up to 3 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 6 carbon atoms each, or by a group of the formula --NR.sup.5 R.sup.6, PA1 wherein PA1 L in this case stands for straight-chain or branched alkoxy with up to 6 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, PA1 T stands for a radical of the formula ##STR6## PA1 wherein PA1 A stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, PA1 D stands for straight-chain or branched alkyl with up to 5 carbon atoms, which is substituted by hydroxy, PA1 E and L are either identical or different and stand for straight-chain or branched alkyl with up to 5 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, PA1 E has the above-mentioned meaning PA1 L in this case stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, PA1 E stands for straight-chain or branched alkyl with up to 4 carbon atoms, or stands for phenyl, which is optionally substituted up to 2 times in an identical manner or differently by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, PA1 L in this case stands for straight-chain or branched alkoxy with up to 5 carbon atoms, or for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy, PA1 T stands for a radical of the formula ##STR7## PA1 wherein PA1 A stands for phenyl, which is optionally substituted by fluorine, chlorine, or methyl. PA1 compounds of the general formula (II) or (III) ##STR8## PA1 A, E, L, and T have the above-mentioned meanings, PA1 and PA1 R.sup.15 stands for straight-chain or branched alkoxycarbonyl with up to 4 carbon atoms, PA1 are either first reacted, using the Grignard or Wittig reaction, in an inert solvent, with further derivatization optionally being carried out according to the customary methods, and then are reduced in inert solvents, PA1 or, in the case of compounds of the general formula (III), direct reductions are carried out, optionally via several steps. PA1 A, E, and L' have the above-mentioned meanings, PA1 R.sup.16 and R.sup.17 are identical or different and stand for straight-chain or branched alkyl with up to 4 carbon atoms, PA1 in inert solvents with oxidants, PA1 and PA1 selectively reducing the alkoxycarbonyl function (CO.sub.2 R.sup.17) to the hydroxy function in a second step. PA1 A and E have the above-mentioned meanings PA1 and PA1 R.sup.18 and R.sup.19 have the meaning given above for R.sup.16 and R.sup.17 and are identical to or different from these, PA1 with ceric(IV) ammonium nitrate into compounds of the general formula (VI) ##STR13## PA1 A, E, R.sup.18, and R.sup.19 have the above-mentioned meanings, PA1 then, by reaction with alkylation agents of the general formula (VII) EQU R.sup.20 --Y (VII) PA1 R.sup.20 stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, PA1 and PA1 Y stands for halogen, preferably for bromine or iodine, PA1 in inert solvents and in the presence of a base, converting them into compounds of the general formula (VIII) ##STR14## PA1 A, E, R.sup.18, R.sup.19, and R.sup.20 have the above-mentioned meanings, PA1 and finally, as described above, carrying out a selective reduction with diisobutylaluminum hydride of the alkoxycarbonyl group --CO.sub.2 R.sup.18 to the hydroxymethylene function, followed by an oxidation to the corresponding aldehyde, likewise as described above, preferably with PCC. PA1 A, E, L, and T have the above-mentioned meanings PA1 and PA1 R.sup.21 denotes a straight-chain or branched alkoxycarbonyl with up to 3 carbon atoms, PA1 first by reduction of the alkoxycarbonyl function, into compounds of the general formula (Ia) ##STR16## PA1 A, E, L, and T have the above-mentioned meanings, PA1 and in a second step, oxidizing the hydroxymethyl function into the aldehyde according to the above-mentioned conditions, preferably with pyridinium chlorochromate (PCC).
Glucagon receptor antagonists of the prior art, such as those described in WO9518153-A and references cited therein, are predominantly peptide analogues of glucagon. They are susceptible to the actions of endogenous proteases, may precipitate antibody production and immune reactions and can be difficult and expensive to manufacture. Such peptides are usually unsuitable for oral delivery.
One non-peptide glucagon receptor antagonist has been reported (Collins, et al; BioMed. Chem Lett. 1992, 2, 915-918). This quinoxaline derivative, CP-99,711, was shown to inhibit glucagon binding and glucagon action in rat liver membrane at micromolar concentrations.
It would be desirable to have inhibitors of CETP which possess valuable pharmacological properties that are superior to those of the state of the art. Certain of the substituted pyridine compounds of the invention are highly effective inhibitors of cholesterol ester transfer proteins (CETP) and stimulate reverse cholesterol transport. They cause a reduction in LDL cholesterol levels in the blood, while at the same time increasing HDL cholesterol levels. They can therefore be used for the treatment of hyperlipoproteinemia or arteriosclerosis.
It would also be desirable to have readily prepared non-peptidic glucagon receptor antagonists which are metabolically more stable than peptidic antagonists of the prior art, and which afford good activity and bioavailability. Certain of the substituted pyridine compounds as well as the substituted biphenyls of the invention are highly effective inhibitors of the glucagon receptor. Accordingly, these compounds may be used to treat glucagon-mediated conditions such as those listed above.